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Metabolic Glycoengineering Introduces Targets for Guided Drug Treatment

By BiotechDaily International staff writers
Posted on 03 Mar 2017
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Image: A ball and stick depiction of a glucose sugar molecule (Photo courtesy of SPL).
Image: A ball and stick depiction of a glucose sugar molecule (Photo courtesy of SPL).
The advanced technique of metabolic glycoengineering was used to insert unusual sugar molecules into the membranes of tumor cells in order to identify the cells for destruction by targeted chemotherapy.

Distinguishing cancer cells from normal cells through surface receptors is vital for cancer diagnosis and targeted therapy. Metabolic glycoengineering of unnatural sugars provides a powerful tool to manually introduce chemical receptors onto the cell surface; however, cancer-selective labeling still remains a great challenge. In a recent paper, investigators at the University of Illinois described the design of sugars that could selectively label cancer cells both in vitro and in vivo.

Specifically, the investigators inhibited the cell-labeling activity of tetraacetyl-N-azidoacetylmannosamine (Ac4ManAz) by converting its anomeric acetyl group to a caged ether bond that could be selectively cleaved by cancer-overexpressed enzymes and thus enabled the overexpression of azido groups on the surface of cancer cells. The azide sugar simply passed through normal cells, but tumor cells metabolized and expressed it on the cell surface, creating specific targets for DBCO "click chemistry" to deliver chemotherapeutic drugs or imaging agents.

Click chemistry, more commonly called tagging, is a class of biocompatible reactions intended primarily to join substrates of choice with specific biomolecules. Click chemistry is not a single specific reaction, but describes a way of generating products that follow examples in nature, which also generates substances by joining small modular units. In general, click reactions usually join a biomolecule and a reporter molecule. Conventional click chemistry requires the presence of a Cu(I) catalyst that is toxic to most organisms and thus, prevents its use in many biological systems. A novel type of copper-free click chemistry is based on the reaction of a cyclooctyne (DBCO) moiety with an azide-labeled reaction partner. This new click chemistry is very fast at room temperature and does not require a cytotoxic Cu(I) catalyst. Cyclooctynes are thermostable with very narrow and specific reactivity toward azides, resulting in almost quantitative yields of stable triazoles. This method requires activation the first biomolecule with DBCO reagent, and the second biomolecule with azide, then mixing the two activated biomolecules to form a conjugate.

The investigators reported in the February 13, 2017, online edition of the journal Nature Chemical Biology that their treatment generated histone deacetylase and cathepsin L-responsive acetylated azidomannosamine, one such enzymatically activated Ac4ManAz analog, which mediated cancer-selective labeling in vivo and which enhanced tumor accumulation of a dibenzocyclooctyne–doxorubicin conjugate via click chemistry. This novel chemotherapeutic agent enabled targeted therapy against LS174T colon cancer, MDA-MB-231 triple-negative breast cancer, and 4T1 metastatic breast cancer in mice.

"We would like to target triple-negative breast cancer. This is a deadly breast cancer, with low survival rates," said Dr. Jianjun Cheng, professor of materials science and engineering at the University of Illinois. "We do not have any targeted therapeutics so far, because it does not have any of the receptors on it that we normally target. Our question was: can we create an artificial receptor? DBCO and azide react with each other with high specificity. We call it click chemistry. The key question is how do you put azide just on the tumor? For the first time, we labeled and targeted tumors with small molecule sugars in vivo, and we used the cancer cell's own internal mechanisms to do it."

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Image: A space-filling model of the anticonvulsant drug carbamazepine (Photo courtesy of Wikimedia Commons).

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